Tri-n-butyltin Hydride-Mediated radical reactions of ortho-and meta-Iodobenzamides to synthesize benzomacrolactams: surprising formation of biphenyl compounds from meta-regioisomers

Abstract

em diferentes condições. Dependendo das condições, os três precursores que contêm o átomo de iodo em posição meta conduziram a uma surpreendente quantidade de compostos bifenílicos, nos quais o átomo de iodo foi substituído por um grupo fenila. O substrato 2-iodobenzamida levou apenas ao produto de hidrogenólise. Nenhum produto ciclizado foi isolado de nenhuma das reações. As estruturas dos compostos bifenílicos inéditos foram elucidadas utilizando-se as espectrometrias de massa, de RMN 1 H e 13 C e experimentos DEPT, COSY, HMQC e HMBC. Foram propostos mecanismos de formação dos compostos bifenílicos e hipóteses para explicar os diferentes comportamentos dos isômeros orto-e metaiodobenzamidas na reação radicalar.Reactions of methyl 4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(3-iodobenzoylamino)-α-Dgalactopyranoside, its gluco epimer, methyl 2,3-di-O-benzyl-6-deoxy-6-(3-iodobenzoylamino)-4-O-(1-pentenyl)-α-D-glucopyranoside and its ortho-regioisomer with tri-n-butyltin hydride were performed in different conditions. Depending on reaction conditions the three meta-iodo isomers gave a surprising amount of biphenyl compounds. The 2-iodo isomer led only to the undesired but expected hydrogenolysis product. No cyclized products were isolated in all the reactions. The structures of the new biphenyl products were elucidated by 1 H and 13 C NMR spectroscopy, DEPT, COSY, HMQC and HMBC experiments and ESI-MS/MS. Mechanisms for the formation of these new biphenyl derivatives and hypotheses to explain the different outcomes for radical reactions of 3-or 2-iodobenzamides were presented. Keywords: biphenyl compounds, aryl radical cyclization, 3-and 2-iodobenzamides IntroductionIn view of the numerous biological activities of macrolactams [1][2][3][4] and the synthetic challenge they present, 3,5 we have studied the Bu 3 SnH-mediated radical cyclization reactions using unsaturated iodides as precursors of macrolactams, 6-12 mainly allyloxy-ortho-iodobenzamides derived from carbohydrates to give benzomacrolactams. [6][7][8][9][10][11] These precursors furnished benzomacrolactams with 11-, 12-and 20-membered ring by regioselective endo aryl radical carbocyclization. [6][7][8][9] The benzamides methyl 4-Oallyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoylamino)-α-D-galactopyranoside (1) and its gluco epimer 2 were found to furnish the benzomacrolactams 3 and 4 owing to 11-endo cyclization in 32% and 40% yield, respectively 6,7 ( Figure 1).Considering that (i) we have been stimulated to study the Bu 3 SnH-mediated radical reactions to construct Faraco et al. 1505 Vol. 20, No. 8, 2009 macrocycles, since there is a limited number of protocols available for the synthesis of large rings using free radical-mediated macrocyclizations, 13 (ii) the endomacrocyclization mode is favoured over the exo, [6][7][8][9]12,[14][15][16][17][18][19][20] (iii) the carbohydrate moiety impose conformational restriction to favour cyclization, [6][7][8][9]12 and (iv) although the majority of fused aromatic macrocycles have been obtained from ortho-halogenobenzene...